Osmotic devices for delivering a beneficial agent to an environment of use are disclosed in Theeuwes et al. U.S. Pat. Nos. 3,845,770 and 3,916,899. These osmotic devices include a semipermeable wall that surrounds a compartment containing an agent. The wall is permeable to the passage of an external fluid, and substantially impermeable to the passage of agent. There is a passageway through the wall for delivering the agent from the device. These devices release agent by fluid being imbibed through the wall into the compartment at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall to produce an aqueous solution containing agent that is dispensed through the passageway from the device. These devices are extraordinarily effective for delivering an agent that is soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid, and for delivering an agent that has limited solubility in the fluid and is admixed with an osmotically effective compound that is soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid. Devices of this type can be swallowed in in order to deliver the agent throughout the transit of the device through the gastrointestinal (GI) tract. Alternatively, devices of his type can be implanted to deliver a drug or other beneficial agent to the body.
In U.S. Pat. No. 4,111,202, the delivery kinetics of the device are enhanced by manufacturing the device with an agent compartment and an osmagent compartment separated by a film, which film is movable from a rested to an expanded state. The device delivers agent by fluid being imbibed through the wall into the osmagent compartment producing a solution that causes the compartment to increase in volume and act as a driving force that is applied against the film. This force urges the film to expand against the agent compartment and correspondingly diminish the volume of this compartment, whereby agent is dispensed through the passageway from the device. While this device operates successfully for its intended use, and while it can deliver numerous difficult to deliver agents, its use is somewhat limited because of the manufacturing steps needed for fabricating and placing the movable film in the device.
In U.S. Pat. No. 4,327,725 Cortese et al provided an osmotic dispensing device for delivering a beneficial agent which, because of its solubility in an aqueous biological fluid is difficult to deliver in meaningful amounts at controlled rates over time. The osmotic device of this patent comprises a semipermeable wall surrounding a compartment containing a beneficial agent that is insoluble to very soluble in an aqueous biological fluid and an expandable hydrogel. In operation, the hydrogel expands in the presence of external fluid that is imbibed into the device and in some operations mixes with the beneficial agents, thereby forming a dispensable formulation that is dispensed through the passageway from the device. This device operates successfully for its intended use, and it delivers many difficult to deliver beneficial agents for their intended purpose.
When administering a drug buccally (i.e., by absorption of the drug through the highly vascularized buccal tissues of the mouth) a number of conditions are present which makes it difficult to effectively deliver drug in a therapeutically effective amount for a prolonged period of time (e.g., for periods greater than several minutes). For example, when a patient is given a drug-containing lozenge, there is a natural tendency to suck and chew on the lozenge thereby effectively reducing the time period during which the drug can be buccally administered by the lozenge. In addition, the action of saliva and swallowing by the patient effectively reduces the concentration of drug along the buccal membranes of the oral cavity and further causes much of the drug to be swallowed, in many cases rendering it inactive upon encountering the low pH environment of the stomach. This has been a particular problem in treating diseases of the mouth which require constant local administration of drug. One such disease condition is candidiasis of the oral cavity. A recent study has shown that 94% of male patients having acquired immunodeficiency syndrome (AIDS) and 72% of those with AIDS-related complex (ARC) had oral candidiasis (Barr & Marder, AIDS: A Guide For Dental Practice, pp. 53-62, 1987). Recommended treatment of oral candidiasis is by continuous dosing of selected anti-fungal agents in the mouth, pharynx and oesophagus. Typically, therapeutically recommended doses of nystatin, amphotericin B or miconazole, either in the form of liquid rinses or slowly dissolving pastilles and tablets have been used to treat oral candidiasis. Unfortunately, when the anti-fungal agents are administered by gargling or with rinses, the anti-fungal agents are cleared from the mouth in a matter of minutes. While the duration of drug delivery is increased somewhat using slowly dissolving pastilles and tablets, typically these release drug for no more than about 15 to 20 minutes. Accordingly, these dosage forms require frequent repetitive dosing (e.g., gargling every five minutes or taking a lozenge 3-4 times per hour) in order to effectively treat the condition.
Another disease condition of the oral cavity for which continuous dosing of drugs has been recommended is in preventing the formation of plaque on teeth. Plaque is the non-calcified accumulation of microorganisms, which are naturally present in the mouth, and byproducts produced by the microorganisms. Plaque adheres tenaciously to the teeth and eventually gives rise to caries in the teeth and/or inflammatory changes in the buccal tissues adjacent the roots of teeth. Because of the bacterial origin of plaque, the drugs used to treat plaque formation have generally been antimicrobial agents such as chlorhexidine digluconate (PERIDEX sold by The Proctor & Gamble Co. of Cincinnati, Ohio); phenolic compounds such as thymol, menthol and eucalyptol (LISTERINE sold by Warner-Lambert Co. of Morris Plains, N.J.); benzophenathradine (VIADENT sold by Vipont Pharmaceutical, Inc. of Fort Collins, Colo.); triclosan and zinc citrate; stannous fluoride; and cetylpyridinium chloride (CEPACOL sold by Marion Merrell Dow of Cincinnati, Ohio and SCOPE sold by The Proctor & Gamble Co. of Cincinnati, Ohio).
Thus, there has been a clear need in the art of treating oral diseases, such as plaque formation and oral candidiasis, for a dosage form which is able to continuously deliver therapeutically effective amounts of a drug or other beneficial agent into the oral cavity for extended periods of time, i.e. periods greater than about 15 to 20 minutes.
One proposed solution to the problem of short duration of drug delivery from rinses, pastilles, and tablets, has been a delivery device comprised of a hydrophilic polymer having a drug dispersed therein. When placed between the cheek and gum of a patient, the hydrophilic polymer absorbs moisture from the buccal membrane, eventually adhering itself to the membrane surface. While it is desirable from the standpoint of patient comfort and convenience to adhere the delivery platform directly to the buccal membrane, this can create a problem when delivering a drug having a tendency to cause irritation. When delivering an irritating drug, these devices tend to magnify the irritation since the device is adhered to the buccal membrane and maintains a high concentration of the irritating drug at a single membrane site.
Thus, there has been a need in the art of treating oral diseases for a dosage form which is able to continuously deliver a potentially irritating drug for extended periods of time without causing irritation.
Another proposed solution to the problem of short duration of drug delivery from rinses, pastilles and tablets, is the use of an osmotic pump to deliver medication to the buccal tissues. There are two broad categories of osmotic pumps: elementary osmotic pumps and osmotic pumps having an expandable push layer or material. Elementary osmotic pumps are typically formed by compressing a tablet of an osmotically active drug (or an osmotically inactive drug in combination with an osmotically active agent or osmagent) and then coating the tablet with a semipermable membrane which is permeable to an exterior aqueous-based fluid but impermeable to the passage of drug and/or osmagent. One or more delivery orifices may be drilled through the semipermeable membrane wall. Alternatively, orifice(s) through the wall may be formed in situ by incorporating leachable pore forming materials in the wall. In operation, the exterior aqueous based fluid is imbibed through the semipermeable membrane wall and contacts the drug and/or salt to form a solution or suspension of the drug. The drug solution or suspension is then pumped out through the orifice as fresh fluid is imbibed through the semipermeable membrane.
While the use of elementary osmotic pumps has proven to be very successful in delivering drugs through the GI tract (i.e., by swallowing the elementary osmotic pump), there are several problems with buccal administration. As with drug-containing lozenges, there is a natural tendency for the patient to suck and chew on the drug-containing elementary osmotic pumps. Chewing in particular tends to compress the deformable membrane wall, thereby squeezing the drug solution or suspension out of the device at an accelerated rate. The duration of drug delivery is therefore severely curtailed. For example, an elementary osmotic pump, originally designed to be swallowed and thereby deliver drug at a relatively constant rate over a period of 12 to 24 hours within the GI tract but which is instead placed in the oral cavity and subjected to patient sucking and chewing, delivers the entire drug dose relatively quickly, sometimes in less than about an hour.
More recently, Barclay et al. in U.S. Pat. No. 5,021,053 disclosed the use of an osmotic pump having an expandable hydrogel "push" layer to deliver medication to the buccal tissues. The Barclay et al. pumps used a gelling/suspending agent mixed into the drug-containing layer to internally support the semipermeable wall of the pump. The gelling agents used in the Barclay et al. pumps are generally water-soluble hydrogels, such as polyethylene oxides. Unfortunately, at least some of these hydrogel gelling/suspending agents are pumped out of the delivery orifice along with the drug. In the case of polyethylene oxides, this tended to give the patient a sticky or slimy mouthfeel.
Although Barclay et al.'s bilayer (i.e., (1) a drug- and gelling agent-containing layer and (2) a hydrophilic polymer push layer) osmotic device represented a significant improvement over the use of elementary osmotic pumps in the oral cavity, the natural tendency for patients to suck on the pump still resulted in premature drug release at least in part because the gelling/suspending agents were unable to withstand the pressures encountered during severe sucking and chewing. For example, in devices designed to deliver drug over a period of about 3 hours, patients who would agressively suck on the Barclay et al. pumps could decrease the duration of drug delivery by as much as 50% (i.e., drug was completely released in about 1.5 hours).
The problem of premature drug release becomes even more significant when using an osmotic pump designed to deliver a drug to the buccal tissues at a high dosage rate and with a minimum start-up time. Such pumps typically have a membrane wall which is extremely thin and porous. While such thin porous membranes are able to achieve the desired short start-up time and high pumping rates, they are extremely fragile and therefore especially susceptable to breaking (e.g., upon chewing) when placed in the oral cavity.